Endometrial receptivity in eutopic

endometrium in patients with

endometriosis: it is not affected,
and let me show you why

mez, Ph.D.,a
Jose Miravet-Valenciano, Ph.D.,a Mara Ruiz-Alonso, Ph.D.,a Eva Go
and Juan A. Garcia-Velasco, M.D.b
a
IGenomix, Valencia; and b IVI Madrid, Rey Juan Carlos University, IdiPAZ, Madrid, Spain

Many women with endometriosis experience compromised fertility. This disease clearly exerts quantitative damage on the ovaries, and
perhaps, also qualitative damage. However, it remains controversial whether endometrial receptivity is compromised. Here we review
the evidence from basic transcriptomic signature data to clinical data from an oocyte donation model and nd support for the concept
that endometrial receptivity is not impaired in women with endometriosis when healthy embryos reach the endometrial cavity. (Fertil
Steril 2017;108:2831. 2017 by American Society for Reproductive Medicine.)
Key Words: Endometrial receptivity, transcriptomic signature, array

Discuss: You can discuss this article with its authors and with other ASRM members at https://www.fertstertdialog.com/users/
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E
ndometriosis is an estrogen- CLINICAL EVIDENCE THAT estingly, implantation rates were signif-
dependent disorder that ENDOMETRIOSIS DOES NOT icantly lower in patients who received
typically affects women of AFFECT ENDOMETRIAL oocytes from women with endometri-
reproductive age, impacting their phys- osis compared to the remaining groups
RECEPTIVITY
ical, mental, and social well-being. An (Table 1, data extracted from Simon
estimated 10% of women suffer from The inuence of endometriosis in the et al., 1994) (2). This nding suggests
endometriosis (1), with symptoms clinical outcome of IVF remains contro- that the apparent infertility in endome-
ranging from practically nonexistent versial. Simon et al. (2) published a com- triosis patients may be caused by certain
to severe chronic pelvic pain, dysmen- parison of IVF outcomes from 96 cycles oocyte alterations that result in embryos
orrhea, and cyclic urinary or bowel in 78 patients with tubal infertility, and that are less likely to implant.
complaints. Endometriosis is historical- from 96 cycles in 96 women with endo- Jones (3) has also reported favor-
ly related to infertility, although the as- metriosis, showing that endometriosis able results of IVF in patients with
sociation remains unclear. Therapeutic patients seemed to have poorer IVF out- endometriosis. During a 3-year period,
approaches are far from curative, and comes in terms of reduced pregnancy follicular stimulation was initiated for
focus on clinical symptom manage- rate per cycle, pregnancy rate per trans- 600 cycles in 319 patients, with endo-
ment rather than curing the disease. fer, and implantation rate. However, metriosis being the primary diagnosis
The increasingly widespread use of when the data were analyzed separately in 20 cycles. The results show good
in vitro fertilization (IVF), especially for patients undergoing oocyte donation IVF outcomes among patients with
oocyte donation techniques, has pro- for different causes, including endome- endometriosis who did not become
vided insights into possible mecha- triosis, IVF outcome (based on the pregnant after surgical and/or endo-
nisms of endometriosis-related same measures as in the previous study) crine therapy. Furthermore, the nd-
infertility. did not differ among the groups. Inter- ings highlight the fact that
endometriosis does not inuence the
Received May 5, 2017; accepted June 1, 2017. sperm/egg interface or the implanta-
J.M.-V. has nothing to disclose. M.R.-A. has nothing to disclose. E.G. has nothing to disclose. J.A.G.-V.
has nothing to disclose. tion mechanism.
Correspondence: Juan A. Garcia-Velasco, M.D., IVI Madrid, Av del Talgo 68, 28023 Madrid, Spain A study published in 1988
(E-mail: Juan.garcia.velasco@ivi.es).
compared IVF outcomes in 136 patients
Fertility and Sterility Vol. 108, No. 1, July 2017 0015-0282/$36.00 (4). The patients were divided into three
Copyright 2017 American Society for Reproductive Medicine, Published by Elsevier Inc. groups: patients with a previous history
http://dx.doi.org/10.1016/j.fertnstert.2017.06.002

28 VOL. 108 NO. 1 / JULY 2017

 Fertility and Sterility

vere stages of the disease. Patients with and without endome-

TABLE 1
triosis did not differ with regards to pregnancy rates (28%
Reproductive outcome according to donors cause of infertility.
versus 29%) or implantation rate (12% and 13%), nor did
these rates differ according to endometriosis stage. These re-
Donors cause Pregnancy rate/ Implantation
of infertility Cycles, n transfer (%) rate (%) sults support the same conclusion drawn in Sung et al. (6)
studynamely, that the adverse effect of endometriosis on
Fertile 34 44 16.2
Polycystic ovaries 58 60.3 23.6
reproductive outcomes is not related to implantation.
Idiopathic infertility 20 45 11.2 A 2007 study by Budak et al. (7) compared outcome pa-
Tubal infertility 27 55.5 18.7 rameters and cumulative pregnancy rates in oocyte donation
Male infertility 28 60.7 19.1 cycles over a period of 10 years. They concluded that this IVF
Endometriosis 11 27.3 7.0a
technique provides similar success rates among women with a
Note: Adapted from Simon et al. (2).
a
P< .05. variety of reproductive disorders, including endometriosis.
Miravet-Valenciano. Endometrial receptivity in endometriosis. Fertil Steril 2017. Their ndings support the idea that oocyte and embryo qual-
ity are the main determinants of IVF success, and cast doubt
on whether implantation is affected by the uterine environ-
of endometriosis but a normal pelvis at the time of oocyte ment of women with endometriosis.
retrieval, those with stage III endometriosis, and those with More recent population-based retrospective cohort
stage IIIIV endometriosis. The results demonstrated that studies have been performed by analyzing data from the So-
the global fertilization rates, per cycle/per transfer pregnancy ciety for Assisted Reproductive Technology. The results
rates, and miscarriage rates in the patients with endometriosis conrm that an endometriosis diagnosis itself is associated
were similar to those of tubal factor patients. This suggested with lower numbers of oocytes, but with a live birth rate
that patients with moderate or severe endometriosis have a similar to with other diagnosis. The lower number of oocytes
compromised reproductive potential, likely due to a reduced retrieved could potentially impact the cumulative live birth
oocyte recovery rate and poor embryo quality. rate among patients with endometriosis, but not the live birth
To exclude all factors that can affect embryo implanta- rate per cycle. Notably, success rates were compromised when
tion except endometrial receptivity, a study was performed a diagnosis of endometriosis was accompanied by other infer-
in which healthy oocyte donors were shared between 25 tility factors (8).
women with stage IIIIV endometriosis and 33 healthy con-
trol women (5). Each healthy donor gave half of their oocytes
to a recipient with severe endometriosis and the other half to a BASIC EVIDENCE THAT ENDOMETRIOSIS
control recipient without endometriosis. All women under- DOES NOT AFFECT ENDOMETRIAL
went a hormone replacement therapy (HRT) cycle at luteal RECEPTIVITY
phase (checked with endometrial biopsy), with only one cycle Many studies suggest that patients with endometriosis have
performed per woman. The groups did not signicantly differ lower implantation rates in either natural or IVF cycles (9
in age intervals, mean numbers of donated oocytes, or 11). Such impaired embryo implantation has been
numbers of embryos transferred. As shown in Table 2 (data associated with altered gene expression in the eutopic
extracted from Daz et al., 2000) (5), the stage IIIIV endome- endometrium of patients with endometriosis compared to
triosis and control groups did not signicantly differ in preg- healthy women (1217). These ndings have led to the
nancy, implantation, or miscarriage rates. These results proposal of several candidate endometrial markers,
suggest that severe endometriosis does not affect implanta- including integrins, glycodelin A, osteopontin,
tion of donated oocytes in HRT cycles, although the power lysophosphatidic acid receptor, hepatocyte growth factor,
of the study was limited (0.57), reducing the ability to draw 17-b-hydroxysteroid dehydrogenase, leukemia inhibitory
nal conclusions. factor, matrix metalloproteinases, endometrial bleeding
Similarly, a slightly earlier study (6) retrospectively factor, and Indian hedgehog (1317). Moreover, ndings
analyzed 239 oocyte recipients who were divided into two indicate altered steroid hormone pathways in women with
groups: patients with and without endometriosis. The group endometriosis compared to healthy women, including
with endometriosis was further subdivided into mild and se- upregulation of estrogen receptors and progesterone
resistance status due to the absence of the b isoform of its
receptor (18, 19).
TABLE 2 Although the results of several studies support this
concept, the single-molecule approach has not reached clin-
Impact of endometriosis in the egg recipient. ical applicability in the eld of endometrial receptivity (20).
Control Stage III/IV The implantation process is complex and the receptive pheno-
Variable group endometriosis type implies the coordination of many biological processes;
Implantation rate (%) 16 14.8 therefore, it seems prudent to approach endometrial recep-
Pregnancy rate (%) 45.5 40 tivity from a holistic point of view. Transcriptomic analyses
Miscarriage rate (%) 26 30 could help us to better understand the behavior of the endo-
Note: All values are percentages. Differences are not signicant. Adapted from Daz et al. (5).
metrium and the consequences of any pathology affecting
Miravet-Valenciano. Endometrial receptivity in endometriosis. Fertil Steril 2017.
it. Along this line, several researchers have used microarray

VOL. 108 NO. 1 / JULY 2017 29

VIEWS AND REVIEWS
technology to detect differential gene expression in the eu-
topic endometrium of women with endometriosis compared
to controls (2124). However, none of these arrays have
shown clinical applicability for detecting fertility.
A molecular tool termed endometrial receptivity analysis
(ERA) can identify a personalized window of implantation
(pWOI) for every woman. This tool evaluates the expressions
of 238 genes related to the endometrial receptivity process,
enabling determination of whether a specic patient requires
a longer or shorter duration of progesterone administration to
reach a receptive status. This represents the rst application of
the concept of personalization to the endometrial factor, al-
lowing synchronization between the blastocyst and a recep-
tive endometriuma key factor in promoting implantation.
The ERA is a clinically validated assay that has helped thou-
sands of women with recurrent implantation failure achieve
pregnancy. Moreover, its accuracy and consistency is superior
to endometrial histology, and its results are completely repro-
ducible for 2940 months after the rst ERA test (25).
To establish whether endometrial receptivity might be
affected by endometriosis, ERA was used to determine
whether different endometriosis stages were associated with
higher rates of non-receptive results compared to women
without endometriosis (26). This study included 17 patients
with different stages of endometriosis (stages IIV) based on
the revised staging system of the American Society for Repro-
ductive Medicine (27), and 5 healthy women. Endometrial bi-
opsies were taken from each woman at day 1820 of a natural
cycle according to Noyes criteria (28), and all samples were
subjected to ERA, obtaining a diagnosis as receptive (R) or
non-receptive (NR). For NR cases, the endometrial status
was further assessed to be pre-receptive (showing a delayed
WOI) or post-receptive (advanced WOI). Interestingly, the re-
sults showed clustering of samples that was not based on
endometriosis stage, but rather on the day of the cycle on
which the samples were taken (day 18 versus days 1920).
Specically, the NR samples grouped together and were all
taken on day 18, while all of the R samples were taken on
days 1920. This correlation was expected, since an earlier
day of the menstrual cycle would logically be associated
with a higher probability of needing more time with proges-
terone administration (pre-receptive prole) to reach a recep-
tive status. In this study, a total of nine clinical variables were
analyzed, but none provided a better explanation for the clus-
tering of the samples than the menstrual cycle day.
Proceeding to deeper gene expression analysis, compari-
sons between the four endometriosis stages and controls re-
vealed that none of the 238 genes present in the ERA array
were signicantly overexpressed or under expressed between
any of these groups. Comparisons between samples taken on
different days of the menstrual cycle (adjusted P value of
< .05) revealed that only 13 genes were differentially regu-
lated: ARG2, CLDN4, HRASLS3, MAOA, EFNA1, RPRM,
DEFB1, S100P, KRT7, BCL6, RARRES3, GDF15, and GA-
BARAPL1. Three of these genes (ARG2, CLDN4, and
S100P) were previously investigated in terms of endometri-
osis and receptivity (2932), but the reports do not identify
the specic mechanisms in which they are involved.
Analysis using a gene ontology approach suggests that if
30
these genes have a clinical effect, it may be minimal.
Notably, endometrial receptivity is a process inuenced by
multiple factors, and this analysis approach is based
exclusively on the expression proles of 238 genes. It is
also important to consider the known inter-individual varia-
tions (33) among endometriosis-affected patients as well as
among healthy patients.
In conclusion, data from clinical IVF and egg donation
programs, and basic data regarding the transcriptomic signa-
ture of the endometrium, seem to indicate that endometrial
receptivity is similar between women with and without endo-
metriosis, and across the different stages of endometriosis.
Clinical data provide valuable information that helps us un-
derstand this process, but may be biased for patient selection.
New molecular tools conrm the information previously ob-
tained from clinical models. For example, results of ERA
conrm that the endometrial receptivity gene signature dur-
ing the window of implantation is similar between infertile
woman with and without endometriosis, and is independent
of endometriosis stage. Moreover, reports in patients under-
going IVF treatment demonstrate that the effect of endometri-
osis is related to embryo and oocyte quality more than to the
endometrial factor itself.
It would be interesting to perform a deeper study,
including more factors involved in receptivity, such as epige-
netic aberrations and pathologic proteomic proles. Such in-
vestigations could improve our knowledge of the enigmatic
disease that is endometriosis. Although the single-molecular
approach has not reached clinical applicability in the eld,
further data must be obtained using ERA and other newly
developed assays before a nal conclusion can be reached
on this subject.
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